Retinal diseases and conditions affect a large population of the United States. Intravitreal (IVT) administration of retinal therapies is a common mode of administration for the treatment of retinal disease. Treatment of diseases of the posterior segment of the eye require the therapeutic to be retained in the posterior compartment of the eye (i.e. the vitreous humor) at a therapeutic concentration for a sufficient period of time to deliver a useful duration of target suppression with a tolerable dosing interval, while also being able to sufficiently diffuse to the target within the diseased-tissue to provide sufficient target occupancy to provide a therapeutic effect. For retinal diseases, a therapeutic generally must diffuse through the vitreal-retinal interface to access the intended target in the diseased tissue, and depending on the specific indication, may need to penetrate deep into retinal tissue, including reaching the retinal pigment epithelial (RPE) layer to reach the intended target at the site of disease.
Aptamers, with a compact shape and typical molecular weight ranging from 8-15 KDa, are of an ideal molecular weight for retinal penetration, but are rapidly cleared from the vitreous due to their low molecular size and weight. To increase vitreal retention, aptamers are typically conjugated to a high molecular weight PEG (e.g. 40 KDa), which due to its large hydrodynamic radius, reduces their clearance rate without greatly compromising their ability to penetrate retinal tissues. PEG does, however, greatly increase the viscosity of a drug formulation, which limits the maximum concentration of drug that can be present in a suitable formulation. Given that only a small volume is administrable by intravitreal injection, use of high molecular weight PEG limits the potential maximum dose that can be administered to the eye in a single injection.
The compositions and methods disclosed herein provide molecules exhibiting improved IVT half-lives by reducing the clearance rate, while maintaining a molecular size that allows for good retinal tissue penetration. In some examples, the compositions and methods disclosed herein provide for molecules with decreased rates of clearance from the vitreous by binding to vitreous components.